Nerve cells play a principal role for sustaining psychoactivities of human beings such as intellectual functions, memory, emotions and behaviors. It has been thought that the differentiation, survival and exhibition of functions of the nerve cells which are the foundations of these psychoactivities need a neurotrophic factor specific for each nerve cell. Among the neurotrophic factors, one of which existence and function have been firstly elucidated is a nerve growth factor (hereinafter simply referred to as “NGF”), and currently, there have been found a brain-derived-neurotrophic factor, neurotrophin-3, neurotrophin-4/5, and the like.
NGF is a neurotrophic factor of a large cellular cholinergic nerve cell of basal portion of the forebrain, so that its association with Alzheimer's dementia has been remarked [Pharmacia, Vol. 22 No. 2, 147-151 (1986), Ronen Seishin Jgaku (Senile Psychiatry), Vol. 3 No. 6, 751-758 (1986)].
Alzheimer's dementia refers to a disease that gives a pathological finding such as senile plaque or Alzheimer's fibrillar changes, which are accompanied by a clinical picture such as developmental disability, manic state, tonic seizures of lower limbs, or epileptic seizure, and is one disease of senile dementia. The Alzheimer's dementia tends to be increasing in recent aging society, so that a larger societal interest has been drawn thereto. However, there has not yet been found a method for ameliorating or treating such symptoms.
In the brain of a patient with Alzheimer's dementia, there has been found a dramatic denaturation, a drastic lowering of the activity of choline acetyl transferase (CAT), in the basal portion of the forebrain centering about Meynert's basal nuclei [Annu. Rev. Neurosci., Vol. 3, 77 (1980)]. In the studies of a rat brain in 1985, there has been elucidated that NGF is a neurotrophic factor at this site of the brain [EMBO J., Vol. 4, 1389 (1985)], so that the association of NGF with this disease has been remarked. In addition, there have been elucidated that in the striate body of the brain of a patient with Huntington's chorea, there are remarkable detachment of GABAergic nerve cell as well as detachment of cholinergic nerve cell, so that NGF also acts on the endogenous cholinergic nerve cell of the striate body [Science, Vol. 234, 1341 (1986)], addressing a possibility that this disease is associated with NGF. The effects of NGF have been studied with an animal such as a rat which can serve as a model for various nerve diseases. There has been reported that the degeneration of the nerve cell can be stopped in a rat if NGF is intracerebrally administered before the degeneration becomes remarkable, and that the lowering of CAT activity is also prevented [J. Neurosci., Vol. 6, 2155 (1986), Brain Res., Vol. 293, 305 (1985), Science, Vol. 235, 214 (1986), Proc. Natl. Acad. Sci. USA, Vol. 83, 9231 (1986)]. Also, it has been proven that NGF is biosynthesized in the peripheral sympathetic nerve-dominant tissues and in the brain, and that each of fibroblasts or astroglia which are interstitial cells for peripheral tissues or brain tissues plays an important role for the NGF biosynthesis [J. Bol. Chem., Vol. 259, 1259 (1984), Biochem. Biophys. Res. Commun., Vol. 136, 57 (1986)]. In addition, it has been elucidated that antigenicity, molecular weight, isoelectric point and biological activity of the fibroblast-producing or astroglia-producing NGF are the same as NGF of conventionally well studied submandibular gland. At the same time, it has been found that a catecholamine such as norepinephrine, epinephrine or dopamine shows enhancing action for NGF production by a test of adding various neurotransmitters to a culture medium of fibroblasts (L-M cells) and astroglia [J. Biol. Chem., Vol. 201, 6039 (1986)].
There has been expectation that NGF can be used as a therapeutic agent for stopping degeneration in a nerve disease in which a site at which NGF acts as a neurotrophic factor is degenerated. In addition, once the cranial nerve cells are degenerated by cebrovascular disorders, cerebral tumor, cerebral apicitus, degenerative disease of head injury, intoxication with an anesthetic, or the like, the degenerated cranial nerve cells would never recover during the life time, whereby various disorders such as emotional disorders and behavioral abnormality are consequently caused in addition to lowering in the intellectual functions and memory disabilities. On the other hand, nerve fiber shows plasticity, that is, when the nerve fiber is damaged, budding takes place from its surrounding healthy fibers, so that a new synapsis is formed in place of the damaged synapsis. Therefore, it has been expected that NGF can be used as a therapeutic agent for promoting restoration and regeneration of nerve functions at this stage.
However, when NGF is applied to a treatment of various nerve diseases, NGF must reach in very close vicinity of nerve cell that requires NGF, and NGF must be transmitted to lesion site of the cranial cell in a case of a disease in the central nervous system. However, NGF cannot be transmitted into the brain through the blood system. This is because the vascular endothelial cells in the brain are bound to each other by adhesion bonding (referred to as brain blood barrier), so that there is a limitation in the transport of a substance other than water, gas or an oil-soluble substance from blood to a brain tissue, whereby a protein (including NGF), which is polymeric substance, cannot pass through the brain blood barrier. There is too large a risk involved in the introduction of NGF directly into the brain by a surgical means, even if the introduction is conducted by the current techniques.
On the other hand, there has been developed a substance for enhancing NGF production, not a direct administration of NGF. Besides the above-mentioned catecholamines, there has been known a substance showing enhancing action for NGF production, such as caffeic acid, or a catechol in which a substituent is introduced into 4-position, including, for instance, as a representative compound, 4-methyl catechol (Japanese Examined Patent Publication No. Hei 5-29207). Also, Japanese Patent Laid-Open No. Hei 2-104568, Japanese Patent Gazette No. 2719042, Japanese Patent Laid-Open No. Hei 8-27086, and Japanese Examined Patent Publication No. Hei 7-110812 each discloses a compound having enhancing activity for NGF production. Most of the compounds, however, have various problems such that the compounds are substances having strong toxicity such as those showing acute toxicity, substances having effective concentration very closely approximating concentration at which toxicity is shown, or substances exhibiting severe adverse actions against the nervous system such as nerve excitation action (for instance, the above-mentioned catecholamine has been known as a representative adrenergic agent), that a concentration range effective for enhancing activity for NGF production is narrow, and that control of dose is difficult. For instance, as to a substance disclosed in Japanese Examined Patent Publication No. Hei 7-110812, there is exhibited twin-peak property between the enhancing activity for NGF production and the compound concentration, so that its control of the dose is difficult to be used as a medicament. In addition, the concentration at which the enhancing activity for NGF production is confirmed for the compounds is disclosed in Japanese Patent Laid-Open No. Hei 2-104568, Japanese Patent Gazette No. 2719042, and Japanese Patent Laid-Open No. Hei 8-27086 is each only one point, so that a concentration range effective for the activity remains unknown. There are various problems as described above, and substances showing enhancing action for NGF production have not yet been actually used.